The Effect of Various Surfactants on Release Behavior of Procainamide HCl from Ethylcellulose Based Matrices

The effect of different kinds of surfactants in various concentrations incorporated in an inert matrix, on the release of procainamide hydrochloride, as a cationic model compound, was investigated in this study. Sodium lauryl sulfate and sodium stearate as anionic surfactants, cetyl pyridinium chloride and cetyltrimethyl ammonium bromide as cationic and span 60 and tween 80 as non-ionic surfactants were selected. Hydrophobic matrices were prepared using procainamide HCl, ethyl cellulose, dicalcium phosphate and different percentages of each surfactant and the dissolution rate of drug from various matrices was determined in pH values1.2 (for 2 h) and 7.2 (up to 10 h). The results showed that incorporation of anionic surfactants in matrix preparations resulted in a remarkable decrease in the release rate of procainamide HCl (P < 0.05), which was attributed to the formation of a poorly soluble complex between the cationic drug and the anionic surfactant. The formation of complex was confirmed by the precipitation titration test. On the other hand, presence of cationic surfactants considerably increased the drug release rate and it was noted that by raising the percentage of surfactant, a faster drug release rate release was achieved. With span 60 there was no change in drug release rate, probably due to its lower wetting capability. While in the case of tween 80, as a hydrophilic non-ionic surfactant, the drug release rate was increased, although statistically not significant. In general, it seems that the influence of cationic and non-ionic surfactants on drug release rate was in accordance with the ability of each surfactant in wetting the matrices and producing a greater number of channels for the dissolution fluid to leach out the drug. Kinetics evaluation of the release profiles showed that the Higuchi equation is the main model, fitting the data.

The Effect of Various Surfactants on Release Behavior of Procainamide HCl from Ethylcellulose Based Matrices

aDepartment of Pharmaceutics, School of Pharmacy,
Shaheed Beheshti University of Medical Sciences,bPharmaceutical
Sciences Research Center, Shaheed Beheshti University of Medical Sciences,
Tehran, Iran.

The effect of different kinds of
surfactants in various concentrations incorporated in an inert matrix, on the
release of procainamide hydrochloride, as a cationic model compound, was
investigated in this study. Sodium lauryl sulfate and sodium stearate as
anionic surfactants, cetyl pyridinium chloride and cetyltrimethyl ammonium
bromide as cationic and span 60 and tween 80 as non-ionic surfactants were
selected. Hydrophobic matrices were prepared using procainamide HCl, ethyl
cellulose, dicalcium phosphate and different percentages of each surfactant and
the dissolution rate of drug from various matrices was determined in pH
values1.2 (for 2 h) and 7.2 (up to 10 h). The results showed that incorporation
of anionic surfactants in matrix preparations resulted in a remarkable decrease
in the release rate of procainamide HCl (P < 0.05), which was attributed to
the formation of a poorly soluble complex between the cationic drug and the
anionic surfactant. The formation of complex was confirmed by the precipitation
titration test. On the other hand, presence of cationic surfactants
considerably increased the drug release rate and it was noted that by raising
the percentage of surfactant, a faster drug release rate release was achieved.
With span 60 there was no change in drug release rate, probably due to its lower
wetting capability. While in the case of tween 80, as a hydrophilic non-ionic
surfactant, the drug release rate was increased, although statistically not
significant. In general, it seems that the influence of cationic and non-ionic
surfactants on drug release rate was in accordance with the ability of each
surfactant in wetting the matrices and producing a greater number of channels
for the dissolution fluid to leach out the drug. Kinetics evaluation of the
release profiles showed that the Higuchi equation is the main model, fitting
the data.

Matrix tablets have long been used to obtain
sustained drug delivery. Embedding or dispersing a drug within hydrophobic
matrices by compression of a physical mixture of polymeric materials and the
medicinal compound is often applied to prepare a sustained release formulation
of a highly water soluble drug (1).

The effect of various
surfactants incorporated in matrix systems on the release rate of? various
drugs has been investigated in previous studies. The addition of surfactant in
matrix formulations has generally resulted in a faster drug release rate (2-4).
Also, a distinct change in the release kinetics has been previously reported
(5). Efentakis reported that the surfactant concentration could change the
release profile from linear to biphasic (5). Incorporation of an anionic
surfactant in the matrix caused the release of a highly water soluble drug to
be linearly related to the square root of time and the release pattern was
shown to be dependent on the surfactant concentration (6). Limited studies have
been conducted, concerning the reduction of drug release rate in the presence
of an oppositely charged surfactant (7-9).

The use of sodium lauryl sulfate (SLS) in
modified hydroxypropyl methylcellulose (HPMC) tablets has been shown to retard
the release rate of chlorpheniramine and resulted in a zero order release
profile (7). Feely and Davis reported that by increasing the amount of SLS
incorporated within a HPMC matrix, the release rate of chlorpheniramine maleate
was reduced (8). In another study, it was found that the release rate of
propranolol decreased as the concentration of anionic surfactant increased.
Also, the use of different ratios of various charged surfactants was able to
change the release rate of the drug (9). Almost all these studies have used
HPMC, a hydrophilic swellable polymer, in the preparation of matrices. Thus, it
seemed important to further investigate this phenomenon in tablet matrices
containing a non-swellable hydrophobic polymer such as ethyl cellulose.

Hence, the effect of various surfactants and
their concentrations on the release behavior of procainamide HCl, as a
water-soluble cationic drug, from inert polymeric matrices was investigated in
the present study.

Matrices containing 100 mg procainamide hydrochloride were
prepared using 40% w/w
ethylcellulose as an inert hydrophobic polymer. Different percentages of
surfactants (lower than CMC), including anionic (sodium lauryl sulfate and
sodium stearate), cationic (cetyl pyridinium chloride and cetyltrimethyl
ammonium bromide) and non-ionic (span 60 and tween 80) were incorporated
within the tablet formulations prepared. Appropriate amounts of dicalcium
phosphate, as a diluent, and 1.5% w/w magnesium stearate, as a lubricant, were
also used in these tablet formulations (Table 1). Matrices were prepared by the
direct compression method, using a single punch machine (Erweka, Germany) with a 9 mm flat-faced punch and die set.

Table 1. Composition of different matrices prepared in this
study

Formulation

Surfactant
(%) w/w

Dicalcium
phosphate (%)

SLS

SS

CPC

CTAB

Span 60

Tween 80

F0

-

-

-

-

-

-

25

F1

5

-

-

-

-

-

20

F2

7

-

-

-

-

-

18

F3

10

-

-

-

-

-

15

F4

15

-

-

-

-

-

10

F5

25

-

-

-

-

-

0

F6

-

5

-

-

-

-

20

F7

-

7

-

-

-

-

18

F8

-

10

-

-

-

-

15

F9

-

15

-

-

-

-

10

F10

-

25

-

-

-

-

0

F11

-

-

5

-

-

-

20

F12

-

-

10

-

-

-

15

F13

-

-

15

-

-

-

10

F14

-

-

-

5

-

-

20

F15

-

-

-

10

-

-

15

F16

-

-

-

15

-

-

10

F17

-

-

-

-

5

-

20

F18

-

-

-

-

10

-

15

F19

-

-

-

-

15

-

10

F20

-

-

-

-

-

5

20

F21

-

-

-

-

-

10

15

F22

-

-

-

-

-

15

10

Dissolution
Studies

The invitro drug release studies from the
various formulations prepared was carried out, using the USP dissolution test
apparatus II (Erweka, Germany), paddle method, at 50?1 rpm. The dissolution
media were 1000 ml 0.1 N HCl (pH=1.2) and phosphate buffer solution (pH=7.2) at
37?0.5?C. Matrices were placed in simulated gastric fluid (pH=1.2) and
maintained for 2 h. After the mentioned time, the dissolution medium was
replaced with the phosphate buffer solution to simulate intestinal fluid and
the release study was continued up to 10 h. Five ml samples were withdrawn at
various time intervals and filtered through 0.45 ?m Millipore filter. Samples
were then analyzed for drug concentration using a UV spectrophotometer (Shimadzu, Japan) at 224 nm and 275 nm for acidic and buffer medium respectively. The mean
of three determinations was used to calculate the drug release from each
formulation. The release kinetics was evaluated by three different models
including the zero order, first order and the Higuchi equation, (considering
the release data up to 60-70%). The selection of the best model was based on
the comparison of the relevant correlation coefficients. The release rate
constants (k), calculated based on the best model, were compared using ANOVA,
with tukey post test.

Precipitation Titration Test

This test was carried out to study the
possible interaction between the cationic drug and anionic surfactants. Ten
mg/ml of procainamide hydrochloride aqueous solution was titrated with the same
concentration of an anionic surfactant aqueous solution and changes in the
solution were observed (6). In addition, an aqueous medium was used as the
blank. Each test was carried out in triplicates.

Results and Discussion

Anionic
Surfactants:

Procainamide
HCl release patterns from tablets containing sodium lauryl sulfate and sodium
stearate are presented in Figures 1 and 2 respectively. According to the
results, incorporation of 5-15% w/w SLS and 5-25% w/w SS in matrix systems,
sustained the release rate of drug in both the acidic and buffer medium. SLS,
as an anionic surfactant with good solubility, can improve the wettability of
tablets in the dissolution medium. Due to this characteristic, a significant
increase in the dissolution rate of lipophilic drugs such as flubiprofen,
griseofulvin, carbamazepine and clofibrate has been reported (10, 11). The
opposite results obtained in this study could be attributed to the formation of
a weak complex between the cationic drug and the anionic surfactant. The
procainamide-SLS complex presumably, with a lower solubility than the free
procainamide, resulted in a noticeable decrease in the dissolution of drug.
This complex could even increase the tortuosity and reduce the porosity of the
matrix system, which is a useful parameter in drug release into the medium (6).
To study the possible interaction between the cationic drug and the anionic
surfactant, precipitation titration tests were carried out. No change occurred
in the blank solution, but existence of the following three stages were clear
within the samples: a primary clear solution, a turbid solution (due to complex
formation) and a secondary clear solution probably because of solubilization of
the complex in surfactant concentrations higher than CMC (6). On the other
hand, there was no change in drug solution titrated with a solution of CPC, the
cationic surfactant, indicating that no complex has been formed.

Increasing the viscosity of the non-ionic polymer in the presence of
anionic surfactants has also been reported earlier (7). In addition, anionic
surfactants could bind to the non-ionic cellulose to form a stronger gel
network (12). Ethylcellulose, used in this study for matrix preparation, is not
soluble and no gel formation occurred around the matrix. Therefore complex
formation could be considered as the underlying mechanism for the observed
reduction in the release rate of procainamide HCl.

As
shown in Figure 1, presence of 25% SLS (F5) within the matrix resulted in an
(p<0.05) increase in the release rate of drug compared to lower percentages
of SLS (F3, F4). It seems that the existence of 25% SLS in tablet formulations
along with lower amounts of dicalcium phosphate (as insoluble filler) caused a
fast disintegration of tablets after 2-3 h, which was also noticeable in the dissolution medium. These results
indicate that the higher concentration of SLS could reduce the release rate
only before the occurrence of tablet disintegration.

It
appears that drug-surfactant interaction over a certain range of surfactant
concentration was an important factor in decreasing the wetting characteristics
of SLS, as well as and the drug release rate.

As shown in
Figure 2, incorporation of 5% SS within the matrix significantly decreased
(P<0.05) the release rate of procainamide HCl, compared to
formulation F0. However, the reduction of drug release rate from
matrices containing 7-25% SS was rather low. In contrast to formulation F5
(containing 25% SLS), the unexpected increase in drug release rate was not
observed in matrix tablets
containing 25% SS (F10). This could be attributed to the lower solubility of
SS,
compared to SLS, which could prevent early tablet disintegration.

Kinetics
evaluation of the related dissolution profiles showed that the release rate
constant for most formulations within this group was significantly lower than
formulation F0 (P < 0.05, Table 2). However, almost all release kinetics
were similar to formulation F0 and in accordance to the Higuchi model.

Table 2. Correlation coefficient (r2) of
different matrices based on various models and the release rate constant (k)

Formulation

Correlation coefficient (r2)

k
(mg.hr -0.5)

SE

P valuea

Zero order

First order

Higuchi equation

F0

0.928

0.866

0.967

36.81

1.90

-

F1

0.958

0.956

0.972

32.35

1.39

0.130

F2

0.961

0.954

0.972

34.59

1.34

0.392

F3

0.945

0.929

0.965

25.66

0.98

0.006

F4

0.946

0.958

0.977

24.24

0.66

0.003

F5

0.957

0.948

0.952

39.95

1.92

0.309

F6

0.901

0.970

0.967

25.37

1.01

0.006

F7

0.946

0.980

0.983

26.35

0.69

0.007

F8

0.949

0.979

0.981

23.41

0.66

0.003

F9

0.954

0.932

0.960

23.97

0.98

0.004

F10

0.939

0.902

0.937

25.53

1.42

0.009

F11

0.911

0.961

0.953

38.80

2.74

0.582

F12

0.905

0.922

0.934

55.08

5.55

0.036

F13

-b

-

-

-

-

-

F14

0.947

0.914

0.954

30.17

2.71

0.115

F15

0.778

0.818

0.838

54.47

6.06

0.049

F16

-

-

-

-

-

-

F17

0.951

0.982

0.981

37.75

1.45

0.714

F18

0.906

0.959

0.965

35.53

1.69

0.641

F19

0.959

0.987

0.988

37.60

1.14

0.739

F20

0.781

0.827

0.860

37.18

4.16

0.939

F21

0.918

0.946

0.950

38.46

2.79

0.651

F22

0.983

0.977

0.977

32.26

1.56

0.137

k was calculated based on the Higuchi model, SE: Standard error of
release rate constant.

a: The release rate constant of each formulation was compared to
Formulation F0 (without surfactant).

b: Release kinetics was not calculated due to a very fast release
of drug.

Cationic
Surfactants:

The
dissolution profiles of procainamide HCl from matrix tablets prepared with
5-15% w/w cetyl pyridinium chloride are presented in Figure 3. It could be seen
that drug release from these matrices is higher than tablets with no surfactant
at both pHs of 1.2 and 7.2. As more surfactant was added to the formulation,
the rate of drug release was increased. The same results were obtained for
matrices prepared in the presence of 5-15% CTAB (Figure 4). Two possible
mechanisms have been postulated for this finding (13). Firstly, it is possible
that the surfactant lowers the interfacial tension between the tablet matrix
and the dissolution medium, and as a result the drug release rate increases.
Secondly, the surfactant could act as a wicking agent, causing the fluid to
enter the dosage form. The surfactant may then dissolve and form pores,?
through which the drug release rate may be affected.

Similar
results were reported by Efentakis et al. (10). They showed that the
incorporation of CPC within hydrophobic matrix formulations accelerated the
flurbiprofen release rate due to the dissolution of surfactant and formation of
pores or channels. The effect of cetyl trimethyl ammonium bromide, as a
cationic surfactant, on the enhancement of propranolol HCl release from
HPMC-Eudragit RS matrices has also been reported in the literature (9).

Table 2 shows
the results obtained from kinetics evaluation of these matrices. The release
kinetics from formulation F0 (without surfactant) and matrices containing CPC
(F11, F12) and CTAB (F14, F15) had a good correlation with the Higuchi model.
The results indicated that the use of higher concentrations of these
surfactants (F12, F15), increased the release rate constant significantly (P
< 0.05), but had no considerable effect on the release kinetics.

Non-ionic
Surfactants:

Figure 5 shows the release
profiles of procainamide HCl from matrices made with 5-15% w/w span 60 as the
non-ionic surfactant. It can be seen that the use of different percentages of
span 60 has no effect on release rate in both the acidic and buffer media and
the release rate constant (k) for tablet formulations F17-F19 is similar to
that of formulation F0 (Table 2). This could be due to the lower solubility and
wettability of this surfactant. In another study, incorporation of span 60 within
the Methocel based matrices even retarded the release rate of ketoprofen (14).
It seems that the higher solubility of procainamide HCl competes with the
hydrophobicity of span 60 (HLB=4.7) and the net result is no change in the
dissolution rate of drug. In order to study the effect of HLB value on the drug release rate, matrices
containing 5-15% tween 80 were also investigated. Based on Figure 6, the
release rate of procainamide HCl from these matrices is slightly higher than
formulation F0 due to the hydrophilicity of tween 80 (HLB=15). This is in
agreement with the results obtained for propranolol HCl matrices containing
tween 65 (9). This indicates that the lipophilicity and hydrophilicity of
surfactant has an important role in the release rate of procainamide HCl. No
statistically significant difference was noted between the release rate
constants of drug from matrices (formulations F20-F22) containing various
percentages of tween 80, (Table 2). It is probable that a higher concentration
of tween 80 within the tablet matrix is required to obtain a higher release
rate of drug. Similar to the matrix tablets prepared without any surfactant,
the best kinetics model for both types of matrices is Higuchi (Table 2).

The effect of
various surfactants (anionic, cationic and non-ionic) in different
concentrations, incorporated in an inert matrix, on the release of procainamide
HCl (as a cationic model compound) was studied in the present investigation.
The release rate of drug was distinctly reduced by incorporation of anionic
surfactants in matrix formulation. This is because SLS and SS are able of
forming poorly water soluble complexes with the drug. The formation of complex
was confirmed by the precipitation titration test. In the case of cationic
surfactants, the drug release rate was significantly increased (P < 0.05).
It is probable that these agents have reduced the interfacial tension and could
also act as a wicking agent, causing the fluid to enter the dosage form.
Non-ionic surfactants had no notable effect on the release rate, but it seems
that the release rate was dependent on the HLB values, as found to increase
slightly in the presence of the hydrophilic non-ionic surfactant. Kinetics
evaluation showed that in almost all matrices the percentage of drug released
was linearly related to the square root of time.

Acknowledgements

The authors
would like to thank the research deputy of Shaheed Beheshti University of
Medical Sciences for providing the financial support for this study.